Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of the arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase A2. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further metabolized to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel diseases. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently several review articles on lipoxygenase inhibitors have been reported. (See H. Masamune and L. S. Melvin, Sr., Annual Reports in Medicinal Chemistry: 24 (1989) pp71-80 (Academic) and B. J. Fitzsimmons and J. Rokach, Leukotrienes and Lipoxygenases (1989) pp427-502 (Elsevier)).
More particularly, International Patent Publications Nos. WO 92/09566 and WO 92/09567, and U.S. Pat. No. 5,187,192, disclose a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme. WO 92/09566 discloses some N-cycloalkenyl-N-hydroxyurea compounds having a heteroaryl substituent on the cycloalkene ring. However, none of the N-(heteroarylcycloalkenyl)-N-hydroxyurea compounds of WO 92/09566 has a further substituent containing an aromatic group attached to the heteroaryl group. In WO 92/09567 and U.S. Pat. No. 5,187,192, none of the N-hydroxyureas has an unsaturated ring (cycloalkene ring) attached to the N-hydroxyurea grouping.